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Diversas cumarinas han sido ampliamente utilizadas como reactivos para la síntesis de furocumarinas, las que poseen interesantes propiedades biológicas. Considerando este antecedente, fue de interés obtener nuevos compuestos benzofurocumarínicos a partir de la Reacción de Williamson, utilizando como reactivo de partida las propias cumarinas, la que supone un ataque nucleofílico de alcohóxidos y fenóxidos sobre halogenuros de alquilo. Con estas premisas, la elección recayó sobre la 2-clorociclohexanona. Se sintetizaron 9 nuevas benzofurocumarinas, las que fueron caracterizadas inequívocamente y evaluadas biológicamente, destacándose las benzofurocumarinas 1 y 2 que resultaron ser más activas y menos tóxicas que el 8-MOP, fármaco utilizado en la terapéutica actual contra el Cáncer, convirtiéndolos en compuestos de un gran perfil farmacológico. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Liver transplantation (OLT) is considered the most efficient therapeutic option for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) in terms of overall survival and recurrence rates, when restrictive selection criteria are applied. Nevertheless, tumor recurrence may occur in 3.5% to 21% of recipients. It usually occurs within 2 years following OLT, having a major negative impact on prognosis. The efficacy of active posttransplantation surveillance for recurrence has not been demonstrated, due to the poor prognosis of recipients with recurrences. Aim: To analyze the clinical, pathological, and prognostic consequences of late recurrence (>5 years after OLT). Method: We analyzed the clinical records of 165 HCC patients including 142 males of overall mean age of 58 ± 6.9 years who underwent OLT between July 1994 and August 2011. Results: Overall survival was 84%, 76%, 66.8%, and 57% at 1, 3, 5, and 10 years, respectively. Tumor recurrence, which was observed in 18 (10.9%) recipients, was a major predictive factor for survival: its rates were 72.2%, 53.3%, 26.7%, and 10% at 1, 3, 5, and 10 years, respectively. HCC recurrence was detected in 77.8% of patients within the first 3 years after OLT. Three recipients (100% males, aged 54–60 years) showed late recurrences after 7, 9, and 10 years. In only one case were Milan criteria surpassed after the examination of explanted liver; no vascular invasion was detected in any case. Recurrence sites were peritoneal, intrahepatic, and subcutaneous abdominal wall tissue. In all cases, immunosuppression was switched from a calcineurin-inhibitor to a mammalian target of rapamycin inhibitor. We surgically resected the extrahepatic recurrences. The remaining recipient was treated with transarterial chemoembolization with doxorubicin-eluting beads and sorafenib. Prognosis after diagnosis of recurrence was poor with median a survival of 278 days (range, 114–704). Conclusions: Global survival, recurrence rate, and pattern of recurrence were similar to previously reported data. Nevertheless, in three patients recurrence was diagnosed >5 years after OLT. Although recurrence was limited and surgically removed in two cases, disease-free survival was poor. Thus, prolonged active surveillance for HCC recurrence beyond 5 years after OLT may be not useful to provide a survival benefit for these patients. [Copyright &y& Elsevier]

Background & Aims: Wilson disease (WD) is a copper metabolism disorder caused by mutations in ATP7B gene, with significant clinical variability. Several studies have analyzed the prevalence and penetrance of mutations. We evaluated both characteristics for our more frequent mutations., Methods: Evaluation of 260 patients from the National Registry: clinical, analytical and genetic data. Estimation of homozygotes and total cases according to Hardy-Weinberg equilibrium and comparison with Registry records., Results: The estimated number of homozygotes were higher than registered: p.Met645Arg (1949/6), p.His1069Gln (20/8), p.Leu708Pro (63/24) and p.Gly869Arg (147/0). p.Met645Arg homozygotes presented less cirrhosis at diagnosis, extrahepatic disease and Kayser-Fleischer ring (KFR) and more presymptomatic cases and diagnosis after 40 years of age than p.Leu708Pro and p.His1069Gln homozygotes. p.Met645Arg homozygotes presented more late diagnosis than p.Met645Arg compound heterozygotes. Compound heterozygotes carrying p.Met645Arg or p.Gly869Arg showed less cirrhosis at diagnosis, KFR and neurological symptoms and more hepatic and presymptomatic cases, despite clearly low ceruloplasmin levels. The estimated prevalence was 1:3.785, predicting more than 10.500 patients., Conclusions: The widespread mutations p.Met645Arg and p.Gly869Arg show low penetrance. WD might be underdiagnosed in Spain due to less severe phenotype of the most frequent mutations, a crucial fact to avoid misdiagnosis and to offer early therapy., Competing Interests: Conflict of interest Victor Vargas: Speaker fees, Alexion Pharma, Consultant (advisory board), Ipsen. Anna Miralpeix: speaker fees from Orphalan. Zoe Mariño: speaker fees from Orphalan and Gilead; advisory fees from Orphalan, Alexion and Deep Genomics; grants from Gilead. The others authors reported no conflict of interest., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: hepatitis C patients loss to follow-up in the health care system has been shown to have negative consequences. This study aimed to investigate this issue as regards primary biliary cholangitis., Methods: the databases (immunology, biochemistry, clinical reports, drug dispensation, appointments) of 4 reference hospitals in Spain (serving a population of 1,450,000 inhabitants) were analyzed. The diagnosis of primary biliary cholangitis was based on an antimitochondrial antibody titer ≥ 1:80, chronically elevated alkaline phosphatase, and the absence of other liver disease. Patients were classified as lost in the absence of reports indicating a diagnosis, specific medical follow-up, and/or treatment with bile salts., Results: a total of 1372 patients with antimitochondrial antibody titers ≥ 1:80 were included between January 2010 and June 2019. A total of 697 (50.8 %) were classified as having primary biliary cholangitis, and 100 patients (14.3 %; 95 % CI: 11.8-17.2) were identified as lost. Of these, 30 were contacted and retrieved. The median age was 70 years, 93 % were female, median alkaline phosphatase was 185 IU/L, 10 % had pruritus, and 27 % had a transient elastography value > 9.5 kPa. The disease was confirmed and ursodeoxycholic acid was started in all 30 patients. Death was liver-related in 6 of the 100 patients classified as lost., Conclusion: up to 14.3 % of patients (1 out of 7) with a definitive diagnosis of primary biliary cholangitis remain undiagnosed, thus preventing monitoring and treatment. More than a quarter are at risk of advanced liver disease and its complications. Patients lost in the system must be identified and retrieved, and searching hospital databases is a suitable approach to meet this goal.

Aim: This study aimed: to develop and validate an LC-MS/MS method for mycophenolic acid, tacrolimus, sirolimus, everolimus and cyclosporin A in oral fluid (OF), as an essential tool to study the usefulness of OF as an alternative matrix for immunossuppressants' therapeutic drug monitoring; and to find the best OF collector for these analytes. Materials & Methods: Chromatographic separation was achieved using an XBridge ® Shield RP18 analytical column maintained at 65ºC, using 2 mM ammonium formate and 0.1% formic acid in water (A) and acetonitrile (B) as mobile phase. OF sample was extracted with solid phase extraction after sonication and protein precipitation. Results & Conclusions: Method validation met all the acceptance criteria. LODs were 0.05-1 ng/ml, and LOQs 0.1-5 ng/ml. Silanized tubes offered the best recoveries. The method was successfully applied to 31 OF specimens, describing everolimus detection in OF for the first time. Conclusion: The proposed method is sensitive enough for the detection of OF trough concentrations in patients receiving immunosuppressants when using an appropriate OF collector.

Introduction: The appropriate selection of hepatocellular carcinoma (HCC) patients who are eligible for transarterial chemoembolization (TACE) remains a challenge. The ART score has recently been proposed as a method of identifying patients who are eligible or not for a second TACE procedure., Objective: To assess the validity of the Assessment for Retreatment with TACE (ART) score in a cohort of patients treated with drug-eluting bead TACE (DEB-TACE)., Secondary Objective: to identify clinical determinants associated with overall survival (OS)., Method: A retrospective, multicentre study conducted in Spain in patients with HCC having undergone two or more DEB-TACE procedures between January 2009 and December 2014. The clinical characteristics and OS from the day before the second DEB-TACE of patients with a high ART score (ART≥2.5) and a low ART score (ART 0-1) were compared. Risk factors for mortality were identified using Cox's proportional hazards model., Results: Of the 102 patients included, 51 scored 0-1.5 and 51 scored ≥2.5. Hepatitis C was more frequent in patients scoring ≥2.5. Median OS from the day before the second DEB-TACE was 21 months (95% CI, 15-28) in the group scoring 0-1.5, and 17 months (95% CI, 10-25) in the group scoring ≥2.5 (P=0.3562). Platelet count and tumour size, but not the ART score, were independent baseline predictors of OS., Conclusions: The ART score is not suitable for guiding DEB-TACE retreatment according to Spanish clinical practice standards., (Copyright © 2017 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.)

Direct-acting antiviral agents (DAA) combining daclatasvir (DCV) have reported good outcomes in the recurrence of hepatitis C virus (HCV) infection after liver transplant (LT). However, its effect on the severe recurrence and the risk of death remains controversial. We evaluated the efficacy, predictors of survival, and safety of DAC-based regimens in a large real-world cohort. A total of 331 patients received DCV-based therapy. Duration of therapy and ribavirin use were at the investigator's discretion. The primary end point was sustained virological response (SVR) at week 12. A multivariate analysis of predictive factors of mortality was performed. Intention-to-treat (ITT) and per-protocol SVR were 93.05% and 96.9%. ITT-SVR was lower in cirrhosis (n = 163) (96.4% vs. 89.6% P = 0.017); the SVR in genotype 3 (n = 91) was similar, even in advanced fibrosis (96.7% vs. 88%, P = 0.2). Ten patients (3%) experienced virological failure. Therapy was stopped in 18 patients (5.44%), and ten died during treatment. A total of 22 patients (6.6%) died. Albumin (HR = 0.376; 95% CI 0.155-0.910) and baseline MELD (HR = 1.137; 95% CI: 1.061-1.218) were predictors of death. DCV-based DAA treatment is efficacious and safe in patients with HCV infection after LT. Baseline MELD score and serum albumin are predictors of survival irrespective of viral response., (© 2017 Steunstichting ESOT.)

Introduction: Anorexia nervosa (AN) is characterised by a refusal to normal body weight accompanied by a marked restriction of food intake, frequently leading to severe malnutrition. In severe malnutrition and wasting syndromes, mucosal atrophy, altered gastrointestinal motility and pancreatic atrophy, which alter digestive function and can exacerbate malnutrition, have been described. The objective of this work was to determine intestinal absorption and pancreatic function in severely malnourished AN patients before and after recovery., Methods: Ten severely malnourished AN women were studied at hospital admittance (body mass index = 11.44-16.16 kg/m(2)) and after weight recovery with artificial nutrition (body mass index ≥ 20 kg/m(2)). A (13)C-labelled triglycerides digestion test, faecal elastase test and d-xylose absorption test were performed., Results: In nine patients, (13)C-labelled triglycerides digestion tests and the faecal elastase and d-xylose tests were normal both before and after weight recovery. In one patient, the results were abnormal, and they led to the detection of a previously undiagnosed celiac disease in addition to her AN., Conclusion: In this series, there was neither intestinal absorption nor pancreatic function disturbances in severely malnourished AN patients either before or after weight recovery. The usefulness of these tests in the differentiation of functional versus structural changes needs further studies., (Copyright © 2013 John Wiley & Sons, Ltd and Eating Disorders Association.)

Percutaneous ablation procedures are minimally invasive treatments for unresectable early stage hepatocellular carcinoma (HCC). These techniques are usually safe, but rare and even fatal complications have been described. We present a fatal result after percutaneous ethanol injection (PEI) for the treatment of a recurrent HCC in a non-cirrhotic liver, with subsequent development of diffuse cholangitis and multiple liver abscesses. Although percutaneous drainage and intensive antibiotic treatment were employed, the patient finally died. We discuss about the etiology and the physiopathology of this rare complication in which the therapeutic options are limited and usually unsuccessful.

We present the case of a liver transplant recipient with alcoholic liver cirrhosis and early-stage hepatocellular carcinoma who developed biopsy-proven acute steroid-resistant rejection 3 months after liver transplantation. After the failure of immunosuppressive therapy with intravenous boluses of 6-methyl-prednisolone and switching of the immunosuppressive regimen to tacrolimus plus mycophenolate mofetil, two doses of intravenous basiliximab were administered four days apart. Clinical, analytical, and biopsy-proven histological response was complete. No basiliximab-related adverse events were detected. Basiliximab may represent an alternative in liver transplantation immunosuppression to treat acute steroid-resistant rejection, without increasing the incidence of infections, neoplasms, or other adverse events, as shown by this case., (Copyright © 2012 Elsevier España, S.L. and AEEH y AEG. All rights reserved.)

Chronic hepatitis C virus (HCV) infection is the main cause of liver cirrhosis and liver carcinoma in western countries. There is evidence that HCV clearance induced by antiviral therapy is beneficial, increasing survival and reducing the complications of cirrhosis. Triple therapy with boceprevir or telaprevir associated with pegylated interferon and ribavirin has increased rates of sustained viral response both in treatment-naïve patients and in those failing previous regimens. Before treating patients with these new molecules, physicians should be familiar with their indications and the regimens to be used. Furthermore, both adverse events and the development of resistances must be monitored. The main aims are careful selection of patients and of the regimen to be used, and achieving adequate adherence to obtain optimal results., (Copyright © 2012 Elsevier España, S.L. y AEEH y AEG. All rights reserved.)

Background: The increasing resistance of several phytopathogenic fungal species to existing agrochemical fungicides has alarmed the worldwide scientific community. In an attempt to overcome this problem, a discriminant model based on substructural descriptors was developed from a heterogeneous database of compounds for the design of, search for and prediction of agrochemical fungicides., Results: The discriminant model classifies correctly 81.95% of the fungicides and 81.54% of the inactive compounds in the training series, with an accuracy of 81.72%. In the prediction series, the percentage of correct classification was 80.59 and 85.56% for fungicides and inactive compounds respectively, with an accuracy of 83.44%. Some fragments were extracted and their contributions were calculated. From the fragments that were determined to make positive contributions to the fungicidal activity, new molecules such as pyrrole derivatives were designed and the probabilities of their being fungicides were calculated. These molecules were correctly classified as potential fungicides., Conclusion: The discriminant model based on substructural descriptors provides a promising methodology for the development of molecular patterns to be used in the design of, search for and prediction of agrochemical fungicides of wide spectrum. This constitutes an alternative for the discovery of compounds that are able to decrease crop losses caused by phytopathogenic fungal species., (Copyright © 2011 Society of Chemical Industry.)

This paper is based on the analysis of 178 polyps of 5 mm or less (polyps we have termed "millimetric") studied in the Endoscopy Department of "La Paz" Hospital, Madrid, during 1993. All polyps fulfilling these characteristics detected during this period are included. The 178 polyps represent 43.4% of all polyps (N = 410) found on colonoscopy in this department in this period. The variables considered in the study protocol include age, sex, localization, morphology and histological examination, with particular attention to high risk histological lesions such as signs of possible malignancy.; we also performed a comparative study between the results obtained from the 178 millimetric polyps (Group I) and the 232 polyps greater than 5 mm (Group II) obtained during the same period. The endoscopic technique for the resection of the polyps was evaluated together with its possible complications. Although there were no significant differences found in respect to age, sex and location, there were morphological differences with a greater number of pediculated or semi-pediculated polyps in Group I whilst there were more sessile polyps in Group II. Adenomatous polyps were the most frequent (84%) in both groups. There was a greater incidence of signs of possible early malignant changes in Group II polyps (10) than in Group I (3.3%). The conclusions which may be drawn from our study are that it is clinically advisable to excise all polyps of 5 mm or less as the frequency of high risk histological changes is not negligible (3.3%), and excision is not problematic as the technique is easy and there have been no complications in our series.

We present the case of a patient with liver cirrhosis secondary to hepatitis C who developed a large (6 cms) hepatocellular carcinoma, diagnosed by raised alphafetoprotein (AFP) levels (> 10000 ng/ml) and imaging techniques (ultrasonography and abdominal CT with and without contrast). During follow-up there was normalization of the AFP levels and disappearance of the lesion on U.S. and CT. Spontaneous regression is exceptional in hepatocellular carcinoma. We describe the characteristics of our case and of the 10 patients described in the literature.

The clinical case of a 73-years old male who was admitted for diarrhea and loss of weight is presented. Barium enema and colonoscopy demonstrated small size polyps in the sigmoid colon, one of which had a histologic diagnosis of adenocarcinoma. Abdominal examination detected a mass in the mesohypogastrium which did not appear to be related to the previous findings. CAT and intestinal transit confirmed a second tumor in the small bowel with the histologic diagnosis of a resected specimen being melanoma.